Adaptive Mechanical Proofreading Toward Robust yet Tunable Humoral Immunity

Adaptive Mechanical Proofreading Toward Robust yet Tunable Humoral Immunity American Physical Society 04/17/2026 10704767 10.1103/vfqt-t3b9 PRX Life 2835-8279 4 2 Qing XuHongda JiangShenshen Wang To reliably transmit information, cells exploit nonequilibrium drives to reduce errors. Kinetic proofreading is a classic mechanism that sharpens ligand discrimination by T lymphocytes, yet it remains unclear whether adaptive immunity relies on kinetic proofreading alone to achieve high fidelity. Here, we propose an alternative: an enhanced form of mechanical proofreading (MPR), in which adaptive force generation during dynamic cell-cell contact enables faithful selection of high-affinity B lymphocytes. Using a coarse-grained model validated by experiments, we show that adaptive MPR, characterized by mechanical feedback between force exertion and contact formation, supports robust discrimination of receptor quality regardless of ligand quantity. While MPR generally balances tradeoffs between speed and fidelity, a negative scaling of contact duration with ligand abundance reveals the presence of feedback. By modulating interactions among distinct ligands that share mechanical load at membrane contacts, adaptive MPR may help mitigate autoimmunity or enhance multivalent vaccines. Overall, this work generalizes proofreading to include cellular designs that operate across scales to reconcile competing functional demands at the systems level.

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